Topical pharmaceutical composition for treatment of anal fissures and hemorrhoids

Abstract

To provide a topical pharmaceutical composition to be applied to the anal region for anal fissures and hemorrhoids, including the postoperative period of hemorrhoidectomy.SOLUTION: A topical pharmaceutical composition comprises an anal dilator, a mucoadhesive polymer and a non-aqueous vehicle.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to topical pharmaceutical compositions for use in the anal area for anal fissures and hemorrhoids, including in the post-operative period following hemorrhoidectomy. [Background technology]

[0002] Anal fissure is an anorectal disease that affects at least 11% of the world's population. The pathology is characterized by a fissure or ulcerated lesion in the skin lining the anal canal or anal verge, often resulting in cramping and bleeding during bowel movements. In addition to anal spasms and bleeding, the main symptoms are pain during bowel movements, itching, irritation of the skin in the anal area, and in some patients, rectal prolapse. The disease can also affect both men and women of all ages, and its most common causes are diet, irritable bowel disease, Crohn's disease, and local trauma.

[0003] Treatment for anal fissures generally involves the use of anesthetics for pain management, the use of healing pads, and waiting for the wound to heal (usually occurring within 6-8 weeks of starting treatment). Depending on the severity of the wound, how deep it is, and the amount of bleeding, the patient may undergo surgery to suture the wound.

[0004] Anal fissure is a condition separate from hemorrhoids and is the dilation of the anorectal veins beneath the mucosa due to increased venous pressure in the hemorrhoids. External hemorrhoids occur below the pectineal line and are covered by scaly or cutaneous epithelium. On the other hand, internal hemorrhoids are located in the internal hemorrhoidal plexus above the pectineal line and are covered by columnar mucosa or transitional epithelium. The main symptoms of patients with hemorrhoidal disease are bleeding, prolapsed papilla, anal pain or discomfort, acute inflammation (thrombosis with or without signs of phlebitis), inflammation or perianal dermatitis, and a feeling of incomplete rectal emptying after defecation.

[0005] Treatment for hemorrhoids usually involves changes in the patient's diet, proper community hygiene, and the use of topical medications such as antiseptics, vasodilators, and anesthetics.

[0006] Other common treatments for hemorrhoids and anal fissures include: Topical corticosteroids can reduce local inflammation. However, this group of drugs is largely ineffective in treating the disease (there is no clinical evidence that they reduce edema, bleeding, or hemorrhoidal protrusion). However, topical corticosteroids carry the risk of infection and skin atrophy as side effects.

[0007] Botulinum toxin has already been used experimentally to treat anal fissures. Laboratory studies have confirmed that its effectiveness is comparable to that of nitric acid ointment. The incidence of side effects is low, but the cure rate is lower and the recurrence rate is higher than with surgical sphincterotomy. The cost of treatment is high, and the dose and technique used are not standardized. Long-term use of botulinum toxin may result in infection, local hematoma, hemorrhoidal thrombosis, and transient urinary incontinence.

[0008] Lidocaine, cinchocaine, and other amide-type anesthetics are used topically to improve symptoms in patients with anal fissures. Amide-type anesthetics are more popular than other anesthetics for topical application in this area because they do not cause allergic reactions or sensitization like ester-type anesthetics that are metabolized to methylparabenzoic acid.

[0009] The use of betanechol in the treatment of anal fissures has produced good clinical responses with a low incidence of complications and side effects. However, laboratory studies comparing betanechol with diltiazem have shown that diltiazem favors successful clinical outcomes in the treatment of anal fissures and hemorrhoids, with longer times to recurrence and fewer recurrences.

[0010] Some calcium antagonists (diltiazem, nifedipine, etc.) are used to treat anal fissures and in the postoperative period of hemorrhoidectomy by reducing the resting pressure of the anal sphincter and promoting wound healing inside and on the edge of the anal cavity. According to a paper published in November 2013 by Dr. Carlos Walter Sobrado of the University of Sao Paulo School of Medicine, local administration of 2% diltiazem in an ointment resulted in a 75% cure rate, whereas local administration of 0.2% nifedipine resulted in an 80%-90% cure rate. In Topical Diltiazem and Betanechol Reduction of Anal Sphincter Pressure (No Side Effects), EACarapeti et al., 1999, the use of topical and oral diltiazem for the treatment of anal fissures was disclosed, revealing that topical administration of 2% concentration of diltiazem is preferable.

[0011] Generally, the active agents are available in the form of individualized ointments consisting of petrolatum jelly preparations and additional ingredients such as aloe vera, astringents and preservatives, which do not solve the symptoms of anal fissures in an effective and lasting manner, but often only temporarily suppress the symptoms of the disease.

[0012] Vaseline (Vaseline®, petrolatum) is the pharmacological excipient most used in the manufacture of topical preparations for the treatment of anal fissures, but it poses significant drawbacks in the treatment of fissures, as detailed below: Petrolatum jelly, despite its good spreading properties, does not adhere well to human skin, is often dripped (especially at temperatures above 35° C.), stains the patient's clothing, and does not allow the active pharmaceutical ingredient to come into contact with human skin for a therapeutically sufficient time.

[0013] Additionally, the need for reapplication of anal fissure and hemorrhoid treatment creams, ointments and gels is a common requirement in the proctology literature.

[0014] When treatment with multiple active ingredients is required, it is advantageous to have the active ingredients in the same formulation for various reasons: (i) the inconvenience of the patient having to double-apply the product to the anal area when obtaining different medications for the different active ingredients (inconvenience of exacerbating the sensitivity of the fissure to the same extent); (ii) when applying a product with separate active ingredients, the patient first deposits a layer of the product containing the first active ingredient on the affected area and then applies a second layer containing the second active ingredient on top of the first layer (obviously, the presence of the first layer may cause a delayed absorption of the active ingredient of the second layer into human skin); (iii) when combining two separate active ingredients with conventional excipients, the end user cannot predict, for example, if the formulation of the active ingredient interacting with the other formulation may interfere with the formulation of the other formulation. Summary of the Invention [Problem to be solved by the invention]

[0015] There is still a need for a topical formulation for anal fissure and hemorrhoids, which contains at least one active ingredient for suppressing pain and at least one active ingredient for relieving anal muscle tone, and these two principles are combined into a stable and suitable formulation.Preferably, the formulation alleviates the inconvenience and inefficiency of Vaseline, such as not dripping after application, making the adhesion to the patient during treatment wider, and stabilizing the active agent. [Means for solving the problem]

[0016] The object of the present invention is a formulation that can combine two or more drugs effective in the treatment of anal fissures, hemorrhoids, and anal area. In certain embodiments, the formulation contains functional excipients for spreading, adhesion, and viscosity suitable for topical application in the anal area. In some aspects, the formulation can be effectively applied once a day.

[0017] Gels have been found to overcome some of the shortcomings of ointments (e.g., containing liquid and / or solid ingredients such as petrolatum). Gels are semi-rigid systems consisting of a three-dimensional network of interlaced particles or macromolecules solvated by a dispersed phase. Gels can be classified as hydrogels, where the continuous phase is aqueous, or as organogels, where the continuous phase is an organic solvent.

[0018] Furthermore, it has been discovered that organogels have improved properties over hydrogels with respect to the active agents contemplated in the present invention. Water in gel formulations has been found to cause undesirable changes such as (i) the creation of an environment conducive to the growth of microorganisms that depend on water for survival; (ii) direct chemical changes in the active agent through reactions such as hydrolysis occurring in the medium; and (iii) physical instability of the formulation.

[0019] The present invention includes a topical pharmaceutical composition suitable for application to the anal area, comprising a topically applied local anesthetic, an anal dilator (including an "active ingredient"), a non-aqueous vehicle, and a mucoadhesive polymer, preferably delivered in a single organogel. In some embodiments, the anal dilator is the only active ingredient. The present invention also includes the following: Step 1: Add the non-aqueous vehicle to a suitable container and heat to 20°C to 50°C; Step 2: Add the active ingredients and shake; Step 3: If necessary, cool the solution to 20°C to 40°C and allow to stand; Step 4: Add a polymer, such as a mucoadhesive polymer, along with a non-aqueous vehicle; Step 5: Optionally, add antioxidant to the product of step 4 and shake until completely homogenized; A method for the preparation of a topical pharmaceutical composition is provided, comprising sequential steps. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention includes topical pharmaceutical compositions suitable for application to the anal area, which include a mucoadhesive polymer, optionally a local anesthetic (e.g., for topical use), an anal dilator, and a vehicle. Typically, the vehicle is non-aqueous. By "anal dilator" is meant any vasodilator that is applicable for topical use and has a local effect on the anal sphincter, such as "nitrates and nitrites" (e.g., nitroglycerin / glyceryl trinitrate (GTN), isosorbide dinitrate, isosorbide mononitrate, butyl nitrite, amyl nitrite) and "calcium channel blockers" (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil).

[0021] "Non-aqueous vehicle" refers to a component of a formulation that serves to form, dissolve, suspend, or homogeneously mix other components to facilitate administration or prepare them into a pharmaceutical form, said component being substantially free of water (e.g., less than 1% v / v, less than 0.5% v / v, or less than 0.1% water). Exemplary compounds as non-aqueous vehicles include caprylic capric triglyceride oil, diethylene glycol monoethyl ether, medium chain mono-diglycerides, castor oil, polyethylene glycol (PEG, e.g., PEG 400), mineral oil, coconut oil, oleic acid, medium chain triglycerides, caprylocaproyl macrogol 8 glycerides, propylene glycol, glycerin, and polyethylene glycol derivatives, alone or in combination. A preferred combination of compounds for the vehicle includes propylene glycol, polyethylene glycol 400, diethylene glycol monoethyl ether, and caprylocaproyl macrogol 8 glycerides.

[0022] Typically, the non-aqueous vehicle used in the formulations of the present invention is propylene glycol and / or polyethylene glycol and / or diethylene glycol monoethyl ether and / or caprylocaproyl macrogol 8 glyceride, often in a proportion of 5.0-90.0% w / w, such as 70-90% w / w or 80-90% w / w. In certain embodiments, the non-aqueous vehicle constitutes 70%-90% w / w of the total composition and includes 10%-20% w / w (14%-18% w / w) PEG 400, 25%-35% w / w (30%-35% w / w) propylene glycol, 20%-30% w / w (20%-25% w / w) diethylene glycol monoethyl ether, and 10%-20% w / w (14%-18% w / w) caprylocaproyl macrogol 8 glyceride.

[0023] More preferably, the present invention is a formulation comprising an organogel for treating anal canal fissures and / or hemorrhoids, the formulation comprising a mucoadhesive platform, a non-aqueous vehicle, diltiazem hydrochloride as an anal dilator, and lidocaine as a local anesthetic.

[0024] An "organogel" is a dispersion of a gelling agent in an organic solvent (eg, a non-aqueous vehicle).

[0025] In one embodiment, diltiazem hydrochloride is an anal dilator, a calcium channel blocker that has been proven effective in reducing resting pressure of the anal sphincter. It has already shown good results in the treatment of chronic anal fissures and in the treatment of hemorrhoids, including in the post-hemorrhoidectomy period. In a study comparing the use of oral and topical diltiazem to reduce maximum anal pressure, the topical administration was more effective, with side effects and cure rates similar to those of topical nitroglycerin.

[0026] In one embodiment, diltiazem is present in a concentration of 0.1-10%, for example 0.5-5%, particularly 1-3%, more particularly 1-2% (eg 1%, 2%).

[0027] In some embodiments, lidocaine hydrochloride or lidocaine base is the anesthetic agent.

[0028] Typically, the concentrations of the two active agents in the formulations of the invention are lidocaine hydrochloride or lidocaine base in a proportion of 0.5% to 5% w / w, and diltiazem hydrochloride in a proportion of 0.1% to 10% w / w. The formulation may also contain a mucoadhesive polymer, i.e., hydroxypropylmethylcellulose and / or sodium alginate and / or hydroxyethylcellulose and / or hydroxypropylcellulose in a proportion of 0.1% to 10% w / w.

[0029] In addition to the combination of the two active agents described above in a single pharmaceutical composition, the present invention also provides for the placement of such active agents in the form of a gel of suitable viscosity, spreading and adhesion properties, which overcomes the problems associated with using petrolatum jelly.

[0030] Bioadhesion is an interfacial phenomenon in which two materials, at least one of which is of biological origin, are held together over time by interfacial forces. The bond may be between an artificial material and a biological substrate, such as the adhesion between a polymer and a biological membrane. Adhesion may be defined as the adhesion produced by contact between a pressure-sensitive adhesive and a surface.

[0031] Mucoadhesion is a property that results from the use of bioadhesive polymers capable of binding to biological substrates by binding to mucosal layers or cell membranes. The property increases the residence time of the formulation at the site of action or absorption and enhances drug contact with the skin and / or mucosal epithelial barrier. Preferably, the mucoadhesive polymers used in the present invention have the ability to enhance residence time on both the skin and the anal mucosa.

[0032] Some examples of adhesive polymers are cellulose derivatives (e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose), carbomers, polyethylene glycols, polycarbophil, polyhydroxyethylmethacrylate, poloxamers, ethylene polyoxides, polyvinylpyrrolidone (povidone), vinyls, polyvinyl alcohol, polyacrylic acid derivatives, pyroxylin, hyaluronic acid, sodium alginate and / or calcium alginate, polysaccharides, acacia, agar, pectin, tragacanth, carrageenan, polypeptides, casein, gelatin, karaya gum, guar gum, xanthan gum, pectin and chitosan). Particularly suitable mucoadhesive polymers include hydroxyethylcellulose, hydroxypropylcellulose, sodium alginate and / or hydroxypropylmethylcellulose.

[0033] Hydroxypropyl methylcellulose (HPMC) is a non-ionic, cold water-soluble, hydrophilic polymer that forms viscous colloidal solutions and is practically insoluble in hot water, chloroform, ethanol (95%) and ether, but soluble in mixtures of ethanol and dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and alcohol. Some hydroxypropyl methylcellulose is soluble in aqueous solutions of acetone, mixtures of dichloromethane and propan-2-ol, and other organic solvents. HPMC exerts some buffering power and can make the system pH independent. Among the various HPMCs, the high viscosity grades HPMC 2208, HPMC 2906 and HPMC 2910 according to the USP XXV / NF XX specifications are the most commonly used to prepare swelling matrix systems.

[0034] Hydroxyethylcellulose (HEC) is a non-ionic ether obtained from cellulose pulp or by processing of cellulose pulp, which is water-soluble at room temperature and is used as a general thickening agent. It is biodegradable, physiologically inert, and forms hydrocolloids with various industrial applications. It is slightly soluble in hot and cold water, producing clear, homogeneous solutions. It is practically insoluble in acetone, ethanol (95%), ether, toluene, and most other organic solvents. In some polar solvents, such as glycol, hydroxyethylcellulose is also soluble or partially soluble. Aqueous solutions of HEC do not effectively change viscosity and are relatively stable at pH 2-12. Hydroxyethylcellulose solutions are relatively unstable below pH 5.0, where hydrolysis occurs. At higher pH, oxidation may occur. Hydroxyethylcellulose is enzymatically degraded, resulting in loss of viscosity of the solution. The enzymes that catalyze this degradation are produced by many bacteria and fungi present in the environment. Therefore, to preserve the excipient for long periods of time, an antimicrobial preservative should be added to the aqueous solution. The polymer can be used with a wide range of water-soluble antimicrobial preservatives. However, the addition of sodium pentachlorophenate to the HEC solution immediately reduces the viscosity.

[0035] Hydroxypropyl cellulose (HPC) is a nonionic partially substituted poly(hydroxypropyl) cellulose ether compatible with cationic surfactants. HPC is highly soluble in water below 38°C and forms a clear colloidal solution. It is insoluble in boiling water and precipitates as swollen flakes at 40-45°C. It is soluble in polar solvents such as short-chain alcohols (ethanol, isopropyl alcohol, etc.) and glycols such as propylene glycol, but insoluble in glycerol. It is also insoluble in aliphatic hydrocarbons such as oils and aromatic hydrocarbons. It is not miscible with methylparaben or propylparaben.

[0036] Typically, hydroxypropyl methylcellulose and / or hydroxyethyl cellulose and / or hydroxypropyl cellulose are combined in proportions of 0.1-10% w / w to provide organogel performance.

[0037] Sodium alginate is a further suitable mucoadhesive polymer. Alginates are linear copolymers of α-L-guluronic acid and β-D-mannonic acid with 1-4 bonds. The substances vary widely in terms of their sequence structure and degree of polymerization, as well as in the ratio between manichronic (M) and glucuronic (G) residues. Thus, the materials can present alternating sequences of MG residues and blocks of two or more residues, M or G sodium alginates being slightly soluble in water and forming viscous colloidal solutions. They are practically insoluble in alcohol (95%), ether, chloroform, alcohol / water mixtures, but with an ethanol content of more than 30% by weight. They are also practically insoluble in other organic solvents with a pH below 3 and in acidified aqueous solutions. The properties of the gel depend on the M / G ratio and the number of crosslinks between the polymer chains. The gels are formed by the formation of a gel consisting of Ca 2+ or Mg 2+ and in the presence of guluronic residue sequences.

[0038] In one example, the formulation of the invention comprises 0.5-10% w / w hydroxypropylcellulose (HPC), in another example 0.5-10% w / w sodium alginate and / or hydroxyethylcellulose are present.

[0039] In another aspect of the invention, a skin-healing adjuvant is used in the preparation of the pharmaceutical composition. Although the element is not essential for wound healing, its use aids in tissue repair and promotes healing with better results. Some examples of skin-healing adjuvants are papain, D-panthenol, propolis, sunflower oil, calcium alginate, grape seed oil, hyaluronic acid, chamomile or Calendula officinalis. In a particular embodiment, the skin-healing adjuvant is D-panthenol, for example, used in a proportion of 0.5-5% w / w.

[0040] The formulations of the present invention may also contain one or more antioxidants. Antioxidants that may be used include alpha tocopherol (0.01-1.0% w / w), gamma and beta tocopherols (0.01-1.0% w / w), ascorbic acid (0.01-1.0% w / w), citric acid monohydrate (0.01-1.0% w / w), ascorbyl palmitate (0.01-1.0% w / w), butylated hydroxytoluene (0.01-1.0% w / w), butylated hydroxyanisole (0.01-1.0% w / w), erythorbic acid (0.01-1.0% w / w), fumaric acid (0.01-1.0% w / w), malic acid (0.01-1.0% w / w), methionine (0.01-1.0% w / w), and the like. Examples of suitable antioxidants include monothioglycerol (0.01-1.0% w / w); sodium metabisulfite and sodium bisulfite (0.01-1.0% w / w); propionyl gallate (0.01-1.0% w / w); sodium ascorbate (0.01-1.0% w / w); sodium formaldehyde sulfoxylate (0.01-1.0% w / w); sodium sulfite (0.01-1.0% w / w); sodium thiosulfate (0.01-1.0% w / w); sulfur dioxide (0.01-1.0% w / w); thymol and polyethylene glycol succinate esters of vitamin E (0.01-1.0% w / w).

[0041] The non-aqueous vehicle is intended to promote the dissolution and solubility of a given active substance, and in certain embodiments, to improve the dermal and transdermal administration of the drug. The mucoadhesive polymer dispersed in the vehicle in question forms an organogel, which is a gel in which the polymer swells and holds the organic solvent in a three-dimensional network. With this in mind, some of the advantages of using a drug given in the form of an organogel are the delivery of the drug in a manner directed to the site of action, longer duration of action, improved dermal and transdermal administration, ease of administration and non-invasiveness. Another advantage of organogel is that due to the adhesive power of the pharmaceutical form to the skin, it can remain for a relatively long period of time before washing and can be contacted in a generally non-irritating manner.

[0042] The active agents lidocaine hydrochloride (an anesthetic) and diltiazem (anal dilator) are the preferred active agents for use in the present invention, although other anesthetics and dilators may be substituted for the agents.

[0043] Alternatives to lidocaine include mepivacaine, etidocaine, lidocaine base, prilocaine, bupivacaine, procaine, chlorprocaine, ropivacaine, tetracaine, cocaine, amethocaine, and cinchocaine. Because ester-based anesthetics are metabolized to methylparabenzoic acid and often cause irritation or allergic reactions, it is preferable to use amide-based anesthetics.

[0044] The anal dilator can be, instead of diltiazem, a drug belonging to the family of dihydropyridines (e.g., nifedipine, felodipine, amlodipine, lacidipine), phenylalkylamines (verapamil), benzodiazepines, and tetralol (mebefradil). Some examples of dilators that do not belong to the class of calcium channel blockers that can be applied in the present invention are topical nitrates, muscarinic agonists, agonists, and adrenergic antagonists (indoramin).

[0045] Additionally, the formulations of the present invention may include aloe vera, which simultaneously acts as a moisturizer, astringent, emollient, anti-inflammatory, soothing and skin protectant against UV rays, and immune stimulant.

[0046] [ Manufacturing process The method for producing the pharmaceutical composition of the present invention preferably comprises the steps of: Step 1: Add the non-aqueous vehicle to a suitable container and heat to 20°C to 50°C; Step 2: Add the active ingredient (diltiazem, lidocaine hydrochloride, etc.) and shake; Step 3: Cool the solution to 20°C to 40°C if necessary and leave it; Step 4: In a separate container, add the polymer, such as a mucoadhesive polymer, to the non-aqueous vehicle and stir until completely dispersed; Step 5: Optionally, add a healing adjuvant along with the product of step 4; Step 6: Optionally, add antioxidant to the product of step 5 and shake until completely homogenized; Step 7: Pour the product of step 3 into the product of step 6 and stir until completely homogenized; It involves sequential steps. A particular composition comprises the following components:

[0047] [Table 1]

Claims

1. In a non-aqueous vehicle: a mucoadhesive polymer, and anal dilator, 13. A topical pharmaceutical composition comprising:

2. 10. The pharmaceutical composition of claim 1, wherein the composition is a semi-solid formulation selected from an ointment, a cream, a gel, an organogel, and a colloid.

3. The pharmaceutical composition of claim 2 , wherein the composition is an organogel.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising a local anesthetic.

5. 5. The pharmaceutical composition of claim 4, wherein the local anesthetic is one or more of mepivacaine, etidocaine, lidocaine base, lidocaine hydrochloride, prilocaine, bupivacaine, procaine, chlorprocaine, ropivacaine, tetracaine, cocaine, amethocaine, and cinchocaine.

6. 6. The pharmaceutical composition of claim 5, wherein the local anesthetic is an amide anesthetic.

7. 7. The pharmaceutical composition of claim 6, wherein the local anesthetic is etidocaine.

8. The pharmaceutical composition of claim 6, wherein the local anesthetic is lidocaine.

9. 9. The pharmaceutical composition of claim 8, wherein the composition comprises 0.5% to 5% w / w lidocaine hydrochloride.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the anal dilator is a calcium channel blocker.

11. 11. The pharmaceutical composition of claim 10, wherein the calcium channel blocker is one or more of diltiazem, nifedipine, felodipine, amlodipine, lacidipine, verapamil, indoramin, and mebefradil.

12. 12. The pharmaceutical composition of claim 11, wherein the calcium channel blocker is nifedipine.

13. 12. The pharmaceutical composition of claim 11, wherein the calcium channel blocker is diltiazem.

14. 14. The pharmaceutical composition of claim 13, wherein the composition comprises 0.1% to 10% w / w diltiazem.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein said local anesthetic and said anal dilator are solubilized in one or more organic solvents and said mucoadhesive polymer is dispersed in said organic solvent.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the mucoadhesive polymer is derived from cellulose.

17. 17. The pharmaceutical composition of claim 16, wherein the mucoadhesive polymer comprises one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, and sodium carboxymethylcellulose.

18. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein the mucoadhesive polymer comprises one or more of polysaccharides, acacia, agar, pectin, sodium alginate, calcium alginate, xanthan gum, tragacanth, carrageenan, polypeptides, casein, gelatin, vinyls, polyvinyl alcohol, povidone, carbomers, polyethylene glycols, poloxamers and polyacrylic acid derivatives.

19. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein the mucoadhesive polymer comprises one or more of sodium carboxymethylcellulose, polyacrylic acid derivatives, chitosan, hyaluronic acid, gellan gum, alginate, pectin, carrageenan, gelatin, acacia gum, tragacanth gum, xanthan gum, poloxamers, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, polyvinyl alcohol, pyroxylin, polyethylene oxide, and povidone.

20. 16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the mucoadhesive polymer is one or more of sodium alginate, hydroxypropyl methylcellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.

21. 21. The pharmaceutical composition of claim 20, wherein the composition contains 0.5% to 10% w / w of the mucoadhesive polymer, hydroxypropylmethylcellulose, hydroxyethylcellulose or mixtures thereof.

22. 21. The pharmaceutical composition of claim 20, wherein the composition contains 0.5% to 10% w / w of the mucoadhesive polymer, hydroxypropyl cellulose, hydroxyethyl cellulose or mixtures thereof.

23. The pharmaceutical composition according to any one of claims 1 to 22, further comprising a healing adjuvant.

24. 24. The pharmaceutical composition of claim 23, wherein the healing adjuvant is one or more of papain, D-panthenol, propolis, sunflower oil or calcium alginate, hyaluronic acid, chamomile, grape seed oil, and Calendula officinalis.

25. The pharmaceutical composition of claim 24, wherein the healing adjuvant is D-panthenol.

26. A pharmaceutical composition according to any one of claims 23 to 25, wherein the composition comprises 0.5% to 7% of a healing adjuvant.

27. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein the non-aqueous vehicle is one or more of caprylcapric triglyceride oil, diethylene glycol monoethyl ether, medium chain monodiglycerides, castor oil, mineral oil, coconut oil, oleic acid, medium chain triglycerides, caprylocaproyl macrogol 8 glycerides, propylene glycol, glycerin and polyethylene glycol derivatives, and polyethylene glycol.

28. 28. The pharmaceutical composition of claim 27, wherein the non-aqueous vehicle is propylene glycol.

29. 28. The pharmaceutical composition of claim 27, wherein the non-aqueous vehicle is diethylene glycol monoethyl ether.

30. 28. The pharmaceutical composition of claim 27, wherein the non-aqueous vehicle is polyethylene glycol (PEG).

31. 28. The pharmaceutical composition of claim 27, wherein the non-aqueous vehicle is caprylocaproyl macrogol 8 glyceride.

32. 32. The pharmaceutical composition of any one of claims 27, 28, 29, 30 or 31, wherein the composition comprises 0.5% to 50% w / w of a non-aqueous vehicle.

33. 33. The pharmaceutical composition of any one of claims 1 to 32, further comprising an antioxidant selected from one or more of alpha, gamma and beta tocopherol; ascorbic acid; citric acid monohydrate; ascorbyl palmitate; butylated hydroxytoluene; butylated hydroxyanisole; erythorbic acid; fumaric acid; malic acid; methionine; monothioglycerol; sodium metabisulfite and bisulfite; propionic acid; propyl gallate; sodium ascorbate; sodium formaldehyde sulfoxylate; sodium sulfite; sodium thiosulfate; sulfur dioxide; thymol and polyethylene glycol succinate of vitamin E.

34. 34. The pharmaceutical composition of claim 33, wherein the composition comprises 0.01 to 1.0 w / w % of an antioxidant.

35. 5. The pharmaceutical composition of claim 4, wherein the local anesthetic is lidocaine hydrochloride; the anal dilator is diltiazem hydrochloride; the non-aqueous vehicle comprises at least one or more of the following: propylene glycol, coconut oil, oleic acid, polyethylene glycol, diethylene glycol monoethyl ether, glycerin, medium chain triglycerides, caprylocaproyl macrogol 8 glycerides; and the mucoadhesive polymer comprises at least one of sodium alginate, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

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